Ferritinophagy‐Mediated Ferroptosis Involved in Paraquat‐Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD

Abstract

Parkinson’s disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.

Cepharanthine Attenuates Early Brain Injury after Subarachnoid Hemorrhage in Mice via Inhibiting 15-Lipoxygenase-1-Mediated Microglia and Endothelial Cell Ferroptosis

“…CEP served an effective protective role by reducing the accumulation of MDA and 4-HNE and recovering the declined GSH content (Figures 4(a) , 4(b) , and 4(d) ). GPx4 and xCT play an important role in resisting lipid peroxidation [ 29 , 30 ]. However, CEP treatment was showed no effective recovery of GPx4 activity in SAH mice after three consecutive days of CEP treatment ( Figure 4(c) ).…”

Liraglutide attenuates hepatic iron levels and ferroptosis in db/db mice

“…Washing with PBS, the fluorescence intensity (Ex/Em = 490 nm/515 nm) was quantified by a multifunctional microplate reader microplate. The intracellular lipid ROS levels were detected by BODIPY 581/591 C11 probe (D3861, Thermo Fisher Scientific) [ 29 ]. Cells were incubated with a 2 μM probe for 37°C for 15 min in the dark.…”

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

“…Recent studies on aging-related diseases have indicated that ferroptosis contributes in the pathogenesis of Alzheimer's disease (230-232), Parkinson's disease (233,234), Huntington's disease (235), Depression (236-238), Osteoarthritis (239), Myocardial ischemia and reperfusion (MI/R) (240)(241)(242), Atherosclerosis (243, 244), and Diabetes (245,246). Notably, quercetin shows iron-chelating activity and effectively decrease iron deposition in the hearts, kidneys and liver of iron-dextran-overloaded mice (247), and protects bone marrow-derived mesenchymal stem cells from erastin-induced ferroptosis through antioxidant pathway (248).…”